Substituted Aromatic Compounds and Related Method for the Treatment of Fibrosis

ABSTRACT

The present invention relates to compounds of: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein
     A is C 5  alkyl, C 6  alkyl, C 5  alkenyl, C 6  alkenyl, C(O)—(CH 2 ) n —CH 3  or CH(OH)—(CH 2 ) n —CH 3  wherein n is 3 or 4;   R 1  is H, F or OH;   R 2  is C 5  alkyl, C 6  alkyl, C 5  alkenyl, C 6  alkenyl, C(O)—(CH 2 ) n —CH 3  or CH(OH)—(CH 2 ) n —CH 3  wherein n is 3 or 4;   R 3  is H, F, OH or CH 2 Ph;   R 4  is H, For OH;   Q is
       1) (CH 2 ) m C(O)OH wherein m is 1 or 2,   2) CH(CH 3 )C(O)OH,   3) C(CH 3 ) 2 C(O)OH,   4) CH(F)—C(O)OH,   5) CF 2 —C(O)OH, or   6) C(O)—C(O)OH;
 
and compositions comprising the same and the method using the same for the prevention or treatment of various fibrotic diseases and conditions in subjects, including pulmonary fibrosis, liver fibrosis, skin fibrosis, renal fibrosis, pancreas fibrosis, systemic sclerosis, cardiac fibrosis or macular degeneration.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of co-pending U.S.application Ser. No. 14/776,328, filed Sep. 14, 2015; which is aNational Stage Application of International Application No.PCT/CA2014/000236, filed Mar. 14, 2014; which claims the benefit of U.S.Provisional Application No. 61/798,269, filed Mar. 15, 2013; all ofwhich are incorporated herein by reference in their entirety.

FIELD OF INVENTION

The present invention relates to substituted aromatic compounds, theirpreparation, compositions comprising the same and the method using thesame for the prevention or treatment of various fibrotic diseases andconditions in subjects, including pulmonary fibrosis, liver fibrosis,skin fibrosis, renal fibrosis, pancreas fibrosis, systemic sclerosis,cardiac fibrosis or macular degeneration.

BACKGROUND OF INVENTION

Fibrosis

Fibrosis is a chronic and progressive process characterized by anexcessive accumulation of extracellular matrix (ECM) leading tostiffening and/or scarring of the involved tissue. It develops throughcomplex cell, extracellular matrix, cytokine and growth factorinteractions. Distinct cell types are involved such as residentmesenchymal cells (fibroblasts and myofibroblasts) and ECM-producingcells derived from epithelial and endothelial cells (through a processtermed epithelial- and endothelial-mesenchymal transition), local orbone marrow-derived stem cells (fibrocytes). Myofibroblasts has longbeen regarded as a major cell type involved in normal wound healing, andas the key effector cell in fibrogenesis. They are highly synthetic forcollagen and other ECM components, and are characterized by the de novoexpression of α-smooth muscle actin (α-SMA) (reviewed in Scotton C. J.and Chambers R. C., 2007). The presence of myofibroblasts in fibroticlesions in animal models of fibrosis correlates with the development ofactive fibrosis, and their persistence and localization to fibrotic fociin human disease is associated with disease progression (Kuhn C. andMcDonald J. A., 1991, and Zhang et al., 1994). Myofibroblasts alsoexhibit an enhanced migratory phenotype (Suganuma et al. 1995) and arecapable of releasing numerous pro-fibrotic mediators.

Fibrotic Diseases

Fibrotic diseases, including pulmonary fibrosis, systemic sclerosis,liver cirrhosis, cardiovascular disease, progressive kidney disease, andmacular degeneration, are a leading cause of morbidity and mortality andcan affect all tissues and organ systems. Fibrotic tissue remodeling canalso influence cancer metastasis and accelerate chronic graft rejectionin transplant recipients. Examples of primary (idiopathic) and secondaryfibrotic disorders with multiple/single organ presentation are listed inTable 1. Nevertheless, despite its enormous impact on human health,there are currently no approved treatments that directly target themechanism(s) of fibrosis.

TABLE 1 Examples of primary (idiopathic) and secondary fibroticdisorders with multiple/single organ presentation. PRIMARY SECONDARYHeart Idiopathic restrictive Coronary artery disease/myocardialinfarction cardiomyopathy Pressure-overload heart (long standingarterial hypertension, valvular disease) Infectious myocarditisAutoimmune diseases Transplant rejection Familial hypertrophiccardiomyopathy Arrhythmogenic right ventricular cardiomyopathyDrug-induced Post-radiation Sarcoidosis Amyloidosis Kidney Idiopathicnephrotic Diabetic glomerulosclerosis syndrome Idiopathic Hypertensivenephrosclerosis membranoproliferative Autoimmune glomerular diseasesglomerulonephritis Drug-induced Post-radiation Amyloidosis Transplantrejection Systemic Systemic sclerosis Graft versus host diseaseSarcoidosis Drug-induced nephrogenic systemic fibrosis AmyloidosisSecondary amyloidosis Post-radiation Toxic environmental exposureStorage disorders (hemochromatosis, glycogenosis, Gaucher's disease,etc.) Lungs Idiopathic pulmonary fibrosis Pneumoconiosis Histiocytosis XInfectious pneumonitis Cryptogenic organizing Tuberculosis pneumoniaHypersensitive pneumonitis Inherited disorders Autoimmune diseasesTransplant rejection Drug-induced Post-radiation Sarcoidosis AmyloidosisLiver Primary biliary cirrhosis Chronic viral hepatitis Primarysclerosing Schistosomiasis cholangitis Alcoholic liver diseaseNonalcoholic fatty liver disease Drug-induced Toxic environmentalexposure Inherited metabolic disorders Autoimmune hepatitis Intestinalbypass Adapted from Vettori S, Gay S, Distler O. Role of MicroRNAs inFibrosis, The Open Rheumatology Journal, 2012, 6, (Suppl 1: M9) 130-139.

Pulmonary Fibrosis

Lung fibrosis, also referred to as pulmonary fibrosis, is a seriousmedical condition that involves scarring of the lung tissue. Thiscondition occurs when the alveoli and interstitial tissue of the lungsbecome inflamed and develop scars on the tissue in an attempt to repairthemselves. Pulmonary fibrosis involves gradual exchange of normal lungparenchyma with fibrotic tissue (fibrous scar). The replacement ofnormal lung with scar tissue causes irreversible decrease in oxygendiffusion capacity. Currently, there is no cure or means by which toreverse this scarring of the lung tissue.

Pulmonary fibrosis can be caused by many conditions which includeschronic inflammatory processes (sarcoidosis, Wegener's granulomatosis),infections, environmental agents (asbestos, silica, exposure to certaingases), exposure to ionizing radiation (such as radiation therapy totreat tumors of the chest), chronic conditions (lupus), and certainmedications (e.g. amiodarone, bleomycin, pingyangmycin, busulfan,methotrexate, and nitrofurantoin).

In a condition known as hypersensitivity pneumonitis, fibrosis of thelung can develop following a heightened immune reaction to inhaledorganic dusts or occupational chemicals. This condition most oftenresults from inhaling dust contaminated with bacterial, fungal, oranimal products.

In some subjects, chronic pulmonary inflammation and fibrosis developwithout an identifiable cause. Most of these subjects have a conditioncalled idiopathic pulmonary fibrosis (IPF). IPF is a chronic progressivepulmonary fibrosis of unknown etiology. Prednisone is the usualtreatment for IPF but it can be treated with other immunosuppressivetherapies with the objective of reduction of inflammation that is theprelude to lung fibrosis. Although prednisone has a modest measurableeffect on improving lung function, the scarce evidence for its long-termefficacy, as well as concerns regarding its safety, limits its use.Indeed most immunosuppressive drugs have little therapeutic effects andlung transplantation may be necessary. Unfortunately, transplants are oflimited success in patients with end-stage long disease and mediansurvival time with patients is four to six years after diagnosis. Assuch, there is need for novel yet efficacious treatment for IPF.

Some clinical trials are ongoing with candidate drugs that specificallyaddress the inhibition or slowing down of fibrosis in the lungs such asinterferon-γ (IFN-γ) and mycophenolate mofetil. Further examplesinclude: pirfenidone which mechanism of action is not well defined butseems to reduce CTGF and has shown some results in clinical phase;substituted biphenyl carboxylic acids which function as lysophosphatidicacid receptor antagonists display significant antifibrotic activity inthe standard pulmonary fibrosis mouse model (bleomycin-induced lungfibrosis). As such, this compound is reported to be in clinical trialsfor the treatment of IPF. Inhibition of protein kinase enzymes withorally active candidate drugs or treatment with orally activeantioxidants provide two treatment approaches for pulmonary fibrosis:multiple receptor tyrosine kinase inhibitor (such as nintedanib) and JNK(kinase) inhibitors (such as tanzisertib). Also, drug candidates for IPFincludes antioxidant N-acetylcysteine. However, to date the progress ofprotein kinase inhibitors and antioxidants have been questionable forthe treatment of IPF due to issues of toxicity and/or efficacy. Proteinkinase enzymes and associated receptors are ubiquitous amongst normaland diseased cell populations and so inhibition may result in toxicityarising in particular amongst rapidly proliferating cell populations.

Additionally, clinical trials are in progress with monoclonal antibodiesthat target different profibrotic proteins (cytokines (CTGF, TGF-β,MCP-1, IL-4 and IL-13), integrins (αvβ6) and enzymes(Lysyloxidase-like-2)) for the treatment of IPF. However, a number ofissues are associated with the development and use of monoclonalantibodies for the treatment of IPF (which apply to other recombinantproteins) which include toxicity (including protein immunogenicity),difficulty of manufacture (batch consistency, scale-up, expense) andadministration (need for refrigeration, not orally active).

Furthermore, though research trials are ongoing, there is no evidencethat any medications can significantly help this condition. Lungtransplantation is the only therapeutic option available in severecases. Unfortunately, transplants are of limited success in patientswith end-stage lung disease. As such, there is a need for novel yetefficacious treatments for IPF. Therefore, there is a need for novel yetconveniently administered (orally active) efficacious synthetic (readilymanufactured) compounds.

Liver Fibrosis

Liver fibrosis or hepatic fibrosis is the excessive accumulation ofextracellular matrix proteins (including collagen), and subsequentscarring process, that occurs in most chronic liver diseases. With time,advanced liver fibrosis results in cirrhosis of the liver. Cirrhosis isthe final phase of the chronic liver disease and is generallyirreversible with a poor long-term prognosis. In the advanced stage, theonly option is the liver transplant. The risk of liver cancer issignificant increased with cirrhosis and cirrhosis may be viewed as apremalignant condition (hepatocellular carcinoma). Indeed, cirrhosis andliver cancer are among the ten causes of death worldwide. As such, thereis a need for novel yet efficacious treatment for liver fibrosis andsubsequent cirrhosis of the liver. Unfortunately, few treatment optionsare available and most often treatment consists of addressing the causesand/or symptoms of liver cirrhosis. No treatment will cure liverfibrosis subsequent scarring and cirrhosis. Liver transplantation is theonly treatment available for patients with advanced stage of fibrosis.Therefore, alternative methods that would be less intrusive are neededto cure, treat, slow the progression of, or prevent liver fibrosis.

Accumulation of fluid in the abdomen (ascites) is a common problemassociated with liver cirrhosis. Treatment options include a low sodiumdiet, diuretics and removal of fluid by insertion of a needle into theabdominal cavity (paracentesis). Cirrhosis of the liver is caused byalcohol abuse, viral hepatitis (B, C and D), non-alcoholic fatty liverdisease (NAFLD) associated with obesity, diabetes, protein malnutrition,coronary artery disease, corticosteroids, auto-immune hepatitis,inherited diseases (cystic fibrosis, alpha-1-antitrypsin deficiency,etc), primary biliary cirrhosis, drug reaction and exposure to toxins.

A limited number of clinical trials are in progress with candidate drugsthat specifically address the inhibition or slowing down of fibrosis inthe liver. However, these trials target specific liver disease such asNASH (Non-alcoholic Steatohepatitis). NASH refers to a combination offatty liver (NAFLD) with inflammation and occurs in individuals whodrink little or no alcohol. Cysteamine is a precursor of the potentliver antioxidant glutathione and increased in vivo production ofglutathione is believed to offer improvement of NASH-related liverdisease. As such, cysteamine is under evaluation in clinical trial inpediatric patients with NASH. Other antioxidants are under evaluationsuch as vitamin E and selenium but their effectiveness for the treatmentof NASH is unknown. Also under evaluation for the treatment of NASH isthe use of anti-diabetic drugs even in patients without diabetes. Thisapproach addresses the fact that most NASH patients have insulinresistance. Once again, there is a need for novel yet convenientlyadministered (orally active) efficacious compound for the treatment ofliver fibrosis, subsequent scarring and liver cirrhosis.

Skin Fibrosis

Skin fibrosis or dermal fibrosis is excessive scarring of the skin, andis a result of a pathologic wound healing response. There is a widespectrum of fibrotic skin diseases: scleroderma, nephrogenic fibrosingdermopathy, mixed connective tissue disease, scleromyxedema, scleredema,and eosinophilic fasciitis. Exposure to chemicals or physical agents(mechanical trauma, burn wounds) are also potential causes of fibroticskin disease. Dermal fibrosis may be driven by immune, autoimmune, andinflammatory mechanisms. The balance of collagen production anddegradation by fibroblasts plays a critical role in the pathophysiologyof fibrotic processes in the skin. Certain cytokines promote wouldhealing and fibrosis, such as transforming growth factor-β (TGF-β) andinterleukin-4 (IL-4), whereas others are antifibrotic, such asinterferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α). Fibroblasts ofnormal skin are quiescent. They synthesize controlled amounts ofconnective tissue proteins and have low proliferative activity.Following skin injury, these cells become activated, i.e. theyproliferate, express α-smooth muscle actin (α-SMA) and synthesize largeamounts of connective tissue proteins. The activated cells are oftencalled myofibroblasts.

Scar formation as part of the wound healing process and whichaccompanies fibrosis is particularly undesired from a cosmeticperspective during skin fibrosis, especially when the scars are formedon the face and/or other exposed parts of the body. Scleroderma refersto skin fibrosis; sclera=hard and derma-skin. However, skin fibrosis mayhave important health consequences, especially if it is part of systemicscleroderma. The latter refers to a connective tissue disease ofauto-immune etiology. Whereas limited cutaneous scleroderma isrestricted to skin on the face and on feet, diffuse cutaneousscleroderma covers more of the skin and may progress to the visceralorgans.

The most popular approach for treating skin fibrosis is the use ofimmunosuppressive therapy. The rationale is that the auto-immuneetiology is responsible for the inflammation aspect of the disease alongwith subsequent tissue damage and fibrosis. Studied drugs includemethotrexate, mycophenolate, mofetil, cyclophosphamide and cyclosporine.Although some improvement has been observed with immunosuppressivetherapy, concerns regarding drug safety along with a lack of definitiveclinical data and demonstratable efficacy, remain.

There is a need to develop efficacious pharmaceutical preparation fortreating skin fibrosis, fibrotic skin diseases and pathological scarringof the skin.

Renal Fibrosis

The kidney is a structurally complex organ that has evolved to perform anumber of important functions: excretion of the waste products ofmetabolism, regulation of body water and salt, maintenance ofappropriate acid balance, and secretion of a variety of hormones andautocoids. Diseases of the kidney are as complex as its structure, buttheir study is facilitated by dividing them by their effects on fourbasic morphologic components: glomeruli, tubules, interstitium, andblood vessels. Unfortunately, some disorders affect more than onestructure and the anatomic interdependence of structures in the kidneyimplies that damage to one almost always secondarily affects the others.Thus, whatever the origin, there is a tendency for all forms of renaldisease ultimately to destroy all four components of the kidney,culminating in chronic renal failure. For instance, in autoimmunediseases such as diabetes mellitus, the kidneys are prime targets tosuffer tissue damage or lesions. Nephrectomy, or kidney removal, aprocedure which is sometimes performed on patients with kidney cancer(e.g. renal cell carcinoma), and may negatively impact kidney functionin the remaining kidney. Chemotherapy and immunosuppressive therapy arealso a source of harmful effects to the kidneys. All these kidneyinjuries result in most of the cases in renal fibrosis. The term “renalfibrosis” means excessive proliferation of cells, hardening tissue andscarring. Renal fibrosis can also result from dialysis following kidneyfailure and catheter placement, e.g., peritoneal and vascular accessfibrosis. Renal fibrosis may also result from a nephropathy such asglomerular diseases (e.g. glomerulosclerosis, glomerulonephritis),chronic renal insufficiency, acute kidney injury, end stage renaldisease and renal failure. Regardless of etiology, all patients withchronic renal disease show a progressive decline in renal function withtime. Fibrosis, so-called scarring, is a key cause of thispathophysiology. Fibrosis involves an excess accumulation ofextracellular matrix (primarily composed of collagen) and usuallyresults in loss of function when normal tissue is replaced with scartissue. The process is largely irreversible, inevitably leading toend-stage renal failure, a condition that requires life-long dialysis orrenal transplantation. Recent major advances have led to a much betterunderstanding of renal fibrosis (or renal tubulointerstitial fibrosis),many problems remain. Little is known about why some wounds heal andothers scar and little about how many putative antifibrotic agents work.

There is a need to develop efficacious pharmaceutical preparation fortreating renal fibrosis.

Cardiac Fibrosis

Cardiac fibrosis, a hallmark of heart disease, is thought to contributeto sudden cardiac death, ventricular tachyarrhythmia, left ventricular(LV) dysfunction, and heart failure. Cardiac fibrosis is characterizedby a disproportionate accumulation of fibrillated collagen that occursafter myocyte death, inflammation, enhanced workload, hypertrophy, andstimulation by a number of hormones, cytokines, and growth factors.

Cardiac fibrosis may also refer to an abnormal thickening of the heartvalves due to inappropriate proliferation of cardiac fibroblasts butmore commonly refers to the proliferation of fibroblasts in the cardiacmuscle. Fibrocyte cells normally secrete collagen, and function toprovide structural support for the heart. When over-activated thisprocess causes thickening and fibrosis of the valve, with white tissuebuilding up primarily on the tricuspid valve, but also occurring on thepulmonary valve. The thickening and loss of flexibility eventually maylead to valvular dysfunction and right-sided heart failure.

The most obvious treatment for cardiac valve fibrosis or fibrosis inother locations, consists of stopping the stimulatory drug or productionof serotonin. Surgical tricuspid valve replacement for severe stenosis(blockage of blood flow) has been necessary in some patients. Also, acompound found in red wine, resveratrol, has been found to slow thedevelopment of cardiac fibrosis. [Olson et al. (2005) “Inhibition ofcardiac fibroblast proliferation and myofibroblast differentiation byresveratrol”. American journal of physiology. Heart and circulatoryphysiology 288 (3): H1131-8; Aubin, et al. (2008) “Female rats fed ahigh-fat diet were associated with vascular dysfunction and cardiacfibrosis in the absence of overt obesity and hyperlipidemia: Therapeuticpotential of resveratrol”. The Journal of Pharmacology and ExperimentalTherapeutics 325 (3): 961-8. More sophisticated approaches of counteringcardiac fibrosis like microRNA inhibition (miR-21, for example) arebeing tested in animal models.

No medication is on the market to prevent or treat cardiac fibrosis andthere is a need to develop efficacious pharmaceutical preparation.

Pancreatic Fibrosis

Chronic pancreatitis (CP) is a progressive inflammatory disease of thepancreas, characterized by irreversible morphologic changes and gradualfibrotic replacement of the gland. Loss of exocrine and endocrinefunction results from parenchymal fibrosis. The primary symptoms of CPare abdominal pain and maldigestion. Grossly, the pancreas may beenlarged or atrophic, with or without cysts or calcifications or tumors.The ducts may be dilated, irregular, or strictured. Essential pathologicfeatures include irregular and patchy loss of acinar tissue, chronicinflammation, ductal changes, and fibrosis. These gross changes areend-manifestations of complex pathogenic mechanisms that are associatedwith gene mutations (including but not limited to cystic fibrosis,cationic trypsinogen gene, CFTR gene mutations in idiopathic acute andchronic pancreatitis, the pancreatic secretory trypsin inhibitor gene,the chymotrypsinogen C gene and the calcium sensing receptor gene,alpha-1 antitrypsine deficiency), metabolic (alcoholic, tobacco smoking,hypercalcemia, hyperlipidemia, chronic renal failure), environmentalfactors (nutritional factors such as micronutrient dificiencies (zinc,copper and selenium; also by postadiation exposure), obstructive(tumors), ischemic (vascular diseases), and autoimmune or associatedwith primary sclerosing cholangitis, Sjögren's syndrome, primary biliarydisorder and type 1 diabetes mellitus. Because of diagnostic andtherapeutic challenges, an interdisciplinary management strategy isrequired.

Macular Degeneration

Most diseases that cause catastrophic loss of vision (e.g. maculardegeneration) do so as a result of abnormal angiogenesis and woundhealing, often in response to tissue ischemia or inflammation.Disruption of the highly ordered tissue architecture in the eye causedby vascular leakage, hemorrhage, and concomitant fibrosis can lead tomechanical disruption of the visual axis and/or biologicalmalfunctioning. The CNS is highly specialized in many ways, includingthe types of inflammatory and wound-healing cells present. Since theretina is part of the CNS, its response to injury utilizes mechanismsvery similar to those observed in the rest of the brain; this is truenot only for the wound-healing response but also for utilization ofmigratory cues functional during development of the neuronal andvascular component of this highly organized tissue (Friedlander M.;Fibrosis and diseases of the eye, J. Clin. Invest. 2007). As discussedbelow, the response of the anterior segment of the eye to wound healingmore closely resembles the response of non-CNS tissues than do suchevents in the posterior segment or the eye. Therefore, I refer to suchwound-healing events in the anterior segment as fibrosis, whereascomparable events in the retina are referred to as gliosis. Althoughsuch distinction is somewhat artificial, it does serve to differentiatebetween the fibroblasts and glial cells that effect the wound-healingand scar-formation events. An increased understanding of inflammation,wound healing, and angiogenesis has led to the development of drugseffective in modulating these biological processes and, in certaincircumstances, the preservation of vision.

Unfortunately, such pharmacological interventions often are too little,too late, and progression of vision loss frequently occurs.

There is need to prevent or treat each fibrotic disease with a safe andefficacious drug.

SUMMARY OF THE INVENTION

More particularly, the present invention concerns novel substitutedaromatic compounds as defined by the formula herein below. Compared toknown aromatic compounds, the present compounds have a longer chain atposition R₂; and this particularity of the present compounds has shownto have favorable and surprising impact on the activity. Therefore, thepresent invention concerns a compound defined by formula:

or a pharmaceutically acceptable salt thereof, wherein

A is C₅ alkyl, C₆ alkyl, C₅ alkenyl, C₆ alkenyl, C(O)—(CH₂)_(n)—CH₃ orCH(OH)—(CH₂)_(n)—CH₃ wherein n is 3 or 4; or is preferably C₅ alkyl, C₅alkenyl, C(O)—(CH₂)_(n)—CH₃ or CH(OH)—(CH₂)_(n)—CH₃ wherein n is 3; oris preferably C₆ alkyl, C₆ alkenyl, C(O)—(CH₂)_(n)—CH₃ orCH(OH)—(CH₂)_(n)—CH₃ wherein n is 4;

R₁ is H, F or OH; or is preferably H or OH;

R₂ is C₅ alkyl, C₆ alkyl, C₅ alkenyl, C₆ alkenyl, C(O)—(CH₂)_(n)—CH₃ orCH(OH)—(CH₂)_(n)—CH₃ wherein n is 3 or 4; or is preferably C₅ alkyl, C₅alkenyl, C(O)—(CH₂)_(n)—CH₃ or CH(OH)—(CH₂)_(n)—CH₃ wherein n is 3; oris preferably C₆ alkyl, C₆ alkenyl, C(O)—(CH₂)_(n)—CH₃ orCH(OH)—(CH₂)_(n)—CH₃ wherein n is 4;

R₃ is H, F, OH or CH₂Ph; or is preferably H, F or OH; or is preferably Hor OH;

R₄ is H, F or OH; or is preferably H or OH;

Q is

-   -   1) (CH₂)_(m)C(O)OH wherein m is 1 or 2,    -   2) CH(CH₃)C(O)OH,    -   3) C(CH₃)₂C(O)OH,    -   4) CH(F)—C(O)OH,    -   5) CF₂—C(O)OH, or    -   6) C(O)—C(O)OH.

In a preferred embodiment, the pharmaceutically acceptable salt of thecompound is sodium, potassium, lithium, ammonium, calcium, magnesium,manganese, zinc, iron, or copper. The preferred pharmaceuticallyacceptable salt of the compound is sodium.

A preferred compound according to the present invention is one of thefollowing compounds:

The present invention also concerns a method for reducing the collagenproduction in cells, comprising contacting the cells with atherapeutically effective amount of a compound of the present invention.The collagen is preferably collagen 1. The collagen production ispreferably the collagen mRNA expression and the production of thecollagen protein. According to a preferred embodiment, the cells are inculture, are part of an organ or are part of an organ that is entirelypart of a live animal, where said animal includes, without limitation, amouse, a rat or a human. In the case that the cells are part of an organthat is entirely part of a live animal, the step of contacting the cellswith a therapeutically effective amount of a compound of the presentinvention is equivalent to administering the compound to the animal. Inthe case that the cells are part of an organ that is entirely part of alive animal and the live animal is a human, the therapeuticallyeffective amount of a compound corresponds to a topical administrationof preferably between about 0.01 to about 10% (w/w), or between about0.1 to 10% (w/w), or between about 1.0 to about 10% (w/w), between about0.1 to about 5% (w/w), or between about 1.0 to about 5% (w/w), or to anoral administration of preferably between about 1 to about 50 mg/kg, orbetween about 1 to 25 mg/kg, or between about 1 to about 10 mg/kg,between about 5 to about 25 mg/kg, or between about 10 to about 20mg/kg. In the case of cultured cells, the therapeutically effectiveamount of a compound corresponds to 0.01 to 0.5 mM, and preferably ofabout 0.2 mM.

The present invention further concerns a method for preventing and/orslowing progression of and/or treating a fibrotic disease in a subjectin need thereof, comprising the administration of a therapeuticallyeffective amount of the compound of the present invention. In apreferred embodiment of the invention, the fibrotic disease is pulmonaryfibrosis, liver fibrosis, skin fibrosis, renal fibrosis, pancreasfibrosis, systemic sclerosis, cardiac fibrosis or macular degeneration.

The compound is preferably administered orally. The subject ispreferably a human. When compound is administered orally and the subjectis a human, the therapeutically effective amount is preferably betweenabout 1 to about 50 mg/kg, or between about 1 to about 25 mg/kg orbetween about 5 to about 25 mg/kg, or between about 1 to about 20 mg/kg,or between about 1 to about 10 mg/kg, or between about 10 to 20 mg/kg.

According to a preferred embodiment of the invention, the fibroticdisease is pulmonary fibrosis. The pulmonary fibrosis is preferablyidiopathic pulmonary fibrosis, sarcoidosis, cystic fibrosis, familialpulmonary fibrosis, silicosis, asbestosis, coal worker's pneumoconiosis,carbon pneumoconiosis, hypersensitivity pneumonitides, pulmonaryfibrosis caused by inhalation of inorganic dust, pulmonary fibrosiscaused by an infectious agent, pulmonary fibrosis caused by inhalationof noxious gases, aerosols, chemical dusts, fumes or vapors,drug-induced interstitial lung disease, or pulmonary hypertension.

In an embodiment, the fibrotic disease is liver fibrosis. According to apreferred embodiment of the invention, the liver fibrosis is resultingfrom a chronic liver disease, hepatitis B virus infection, hepatitis Cvirus infection, hepatitis D virus infection, schistosomiasis, alcoholicliver disease or non-alcoholic steatohepatitis, obesity, diabetes,protein malnutrition, coronary artery disease, auto-immune hepatitis,cystic fibrosis, alpha-1-antitrypsin deficiency, primary biliarycirrhosis, drug reaction and exposure to toxins.

In an embodiment, the fibrotic disease is skin fibrosis. According to apreferred embodiment of the invention, the skin fibrosis is scarring,hypertrophic scarring, keloid scarring, dermal fibrotic disorder, woundhealing, delayed wound healing, psoriasis or scleroderma. Said scarringmay derived from a burn, a trauma, a surgical injury, a radiation or anulcer. Said ulcer can be a diabetic foot ulcer, a venous leg ulcer or apressure ulcer.

When the fibrotic disease is a skin fibrosis, the compound is preferablyadministered topically or orally. When the compound is administeredtopically and the subject is human, the therapeutically effective amountof the compound of the present invention is preferably between about0.01 to about 10% (wlw), or between about 0.1 to 10% (w/w), or betweenabout 1.0 to about 10% (wlw), between about 0.1 to about 5% (w/w), orbetween about 1.0 to about 5% (w/w),. When administered orally, thetherapeutically effective amount of the compound of the presentinvention is preferably between about 1 to about 50 mg/kg, or betweenabout 1 to 25 mg/kg, or between about 1 to about 10 mg/kg, between about5 to about 25 mg/kg, or between about 10 to about 20 mg/kg, and thesubject is human.

In an embodiment, the fibrotic disease is kidney fibrosis. According toa preferred embodiment of the invention, the kidney fibrosis isresulting from dialysis following kidney failure, catheter placement, anephropathy, glomerulosclerosis, glomerulonephritis, chronic renalinsufficiency, acute kidney injury, end stage renal disease or renalfailure.

According to a preferred embodiment, the invention also concerns amethod for antagonizing collagen secretion or collagen deposition in anorgan, such as the lung, the liver, the skin or the heart, of a mammalcomprising the administration of a therapeutically effective amount of acompound of the present invention to the mammal that is in need thereof,wherein the organ is kidney, lung, liver, skin or heart. The mammal thatis in need thereof is a mammal that is subject to an excessive collagensecretion or collagen deposition in an organ such as the kidney, thelung, the liver, the skin or the heart. Usually, the excessive collagensecretion or collagen deposition in an organ results from an injury oran insult. Such injury and insult are organ-specific and are describedherein in details in the background section and in the wholespecification. The therapeutically effective amount describedhereinabove in detail also applies to the present method forantagonizing collagen secretion or collagen deposition in an organ. Theroute of administration described herein also applies to the presentmethod. The compound is preferably administered over a sufficient periodof time to antagonize the level of collagen deposition in the organ,completely or partially. The term “antagonizing” used herein is intendedto mean “decreasing” or “reducing”. A sufficient period of time can beduring one week, or between 1 week to 1 month, or between 1 to 2 months,or 2 months or more. For chronic condition, the compound of the presentinvention can be advantageously administered for life time period.

In an embodiment, the fibrotic disease is cardiac fibrosis. In thisembodiment, the therapeutically effective amount is preferably betweenabout 1 to about 50 mg/kg, and preferably or between about 1 to 25mg/kg, or between about 1 to about 10 mg/kg, between about 5 to about 25mg/kg, between about 5 to about 20 mg/kg, or between about 10 to about20 mg/kg. The compound is preferably administered orally. The subject ispreferably a human.

In another preferred embodiment, the compound of the present inventioncan be administered in combination with a therapeutically effectiveamount of second compound where the second compound is preferably atherapeutic agent know for being effective in preventing or treating orpotentially preventing or treating a fibrotic disease. According to anembodiment of the present invention, the compound can be administered incombination with a therapeutically effective amount of second compound,the second compound is an immunosuppressive drug, an anti-inflammatorydrug, a cytokine, a monoclonal antibody, a multiple receptor tyrosinekinase inhibitor, an antioxidant, an enzyme inhibitor, an integrininhibitor, an hypertensive inhibitor, a lipid receptor modulator or athiazolindione.

In addition to the previous embodiments of dosages, for all abovementioned fibrotic diseases, when the compound of the present inventionis orally administered to a human, the therapeutically effective amountof a compound corresponds to preferably between about 0.01 to about 10%(w/w), or between about 0.1 to 10% (w/w), or between about 1.0 to about10% (w/w), between about 0.1 to about 5% (w/w), or between about 1.0 toabout 5% (w/w). In all above mentioned fibrotic diseases, when thecompound of the present invention is orally administered to a human, thetherapeutically effective amount of a compound corresponds preferablybetween about 1 to about 50 mg/kg, or between about 1 to 25 mg/kg, orbetween about 1 to about 10 mg/kg, between about 5 to about 25 mg/kg, orbetween about 10 to about 20 mg/kg.

The present invention also concerns a kit for preventing and/or slowingprogression of and/or treating fibrotic disease in a subject in needthereof. The kit comprises a compound represented by the formula:

or a pharmaceutically acceptable salt thereof, wherein

A is C₅ alkyl, C₆ alkyl, C₅ alkenyl, C₆ alkenyl, C(O)—(CH₂)_(n)—CH₃ orCH(OH)—(CH₂)_(n)—CH₃ wherein n is 3 or 4; or is preferably C₅ alkyl, C₅alkenyl, C(O)−(CH₂)_(n)—CH₃ or CH(OH)—(CH₂)_(n)—CH₃ wherein n is 3; oris preferably C₆ alkyl, C₆ alkenyl, C(O)—(CH₂)_(n)—CH₃ orCH(OH)—(CH₂)_(n)—CH₃wherein n is 4;

R₁ is H, F or OH; or is preferably H or OH;

R₂ is C₅ alkyl, C₆ alkyl, C₅ alkenyl, C₆ alkenyl, C(O)—(CH₂)_(n)—CH₃ orCH(OH)—(CH₂)_(n)—CH₃ wherein n is 3 or 4; or is preferably C₅ alkyl, C₅alkenyl, C(O)—(CH₂)_(n)—CH₃ or CH(OH)—(CH₂)_(n)—CH₃ wherein n is 3; oris preferably C₆ alkyl, C₆ alkenyl, C(O)—(CH₂)_(n)—CH₃ orCH(OH)—(CH₂)_(n)—CH₃wherein n is 4;

R₃ is H, F, OH or CH₂Ph; or is preferably H, F or OH; or is preferably Hor OH;

R₄ is H, F or OH; or is preferably H or OH;

Q is

-   -   1) (CH₂)_(m)C(O)OH wherein m is 1 or 2,    -   2) CH(CH₃)C(O)OH,    -   3) C(CH₃)₂C(O)OH,    -   4) CH(F)—C(O)OH,    -   5) CF₂—C(O)OH, or    -   6) C(O)—C(O)OH;

and instructions for administering a therapeutically effective amount ofthe compound to the subject suffering from said fibrotic disease. In apreferred embodiment of the invention, the fibrotic disease is pulmonaryfibrosis, liver fibrosis, skin fibrosis, renal fibrosis, pancreasfibrosis, systemic sclerosis, cardiac fibrosis or macular degeneration.The kit may also comprises instructions for administering any of theabove-disclosed therapeutically effective amount of the compound fororal administration.

For all fibrotic diseases, the kit preferably further comprisesinstructions for administering between about 1 to about 50 mg/kg of thecompound daily and orally to the subject who is a human.

When the fibrotic disease is skin fibrosis, the kit preferably furthercomprises instructions suggesting administering topically and dailybetween about 0.01 to about 10% (w/w) of the compound to the subject whois a human; or instructions suggesting administering orally and dailybetween about 1 to about 50 mg/kg of the compound to the subject who isa human.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 illustrates the glomerular filtration rate (GFR) function indb/db diabetic mouse compared to C57BL/6 mice (control mice), and indb/db diabetic mouse following oral treatment with Compound 1 at a doseof 10 and 50 mg/kg.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term “alkyl” is intended to include both branchedand straight chain saturated aliphatic hydrocarbon groups having five orsix carbon atoms. Examples of alkyl defined above include, but are notlimited to, n-pentyl, n-hexyl, isopentyl, isohexyl, t-pentyl andt-hexyl. Similarly, as used herein, the term “alkenyl” is intended toinclude unsaturated straight or branched chain hydrocarbon groups havingfive or six carbon atoms, and in which at least two carbon atoms arebonded to each other by a double bond, and having E or Z regiochemistryand combinations thereof. Examples of alkenyl defined above include, butare not limited to, 1-pentenyl, 2-pentenyl, 1-hexenyl and 2-hexenyl.

The compounds of the present invention, or their pharmaceuticallyacceptable salts may contain one or more asymmetric centers, chiral axesand chiral planes, and may thus give rise to enantiomers, diastereomersand other stereoisomeric forms and subsequently may be defined in termsof absolute stereochemistry such as (R)- or (S)-. The present inventionis therefore intended to include all such possible isomers, as well astheir racemic and optically pure forms. Optically active (+) and (−),(R)- and (S)-, or (D)- and (L); isomers may be prepared using chiralsynthons or chiral reagents or resolved using conventional techniques,such as reverse phase HPLC. The racemic mixtures may be prepared andsubsequently separated into individual optical isomers or these opticalisomers may be prepared by chiral synthesis. The enantiomers may beresolved by methods known to those skilled in the art, for example byformation of diastereoisomeric salts which may then be separated bycrystallization, gas-liquid or liquid chromatography, or selectivereaction of one enantiomer with an enantiomer specific reagent.

As used herein, the term “pharmaceutically acceptable salt” is intendedto mean those salts which retain the biological effectiveness andproperties of the free acids, which are not biologically or otherwiseundesirable. These salts are derived from addition of an inorganic baseor an organic base to the organic acid. Salts prepared from inorganicbases include, but are not limited to, the sodium, potassium, lithium,ammonium, calcium, magnesium, manganese, zinc, iron, copper and thelike. Salts prepared from organic bases include, but are not limited to,salts of primary, secondary and tertiary amines, substituted aminesincluding naturally occurring substituted amines, cyclic amines andbasic amino acids (lysine, arginine, and histidine). Examples ofpharmaceutically acceptable salts are also described, for example, inBerge et al., “Pharmaceutical Salts”, J. Pharm. Sci. 66, 1-19 (1977).Preferred salt of the compound of the present invention are sodium,potassium, lithium, ammonium, calcium and magnesium; and more preferablysodium. Pharmaceutically acceptable salts may be synthesized from theparent compound that contains an acid moiety by conventional chemicalmethods. Generally, such salts are prepared by reacting the free acidform of these compounds with a stoichiometric amount of the appropriatebase in water or in an organic solvent, or in an aqueous/organic solventmixture. Salts may be prepared in situ, during the final isolation orpurification of the compound or by separately reacting the purifiedcompound of the invention in the free acid form with the desiredcorresponding base, and isolating the product salt.

As indicated herein above and exemplified herein below, the compound ofthe invention has beneficial pharmaceutical properties and may haveuseful pharmaceutical applications in the prevention and/or treatment ofvarious fibrotic diseases and related conditions in a subject. Medicaland pharmaceutical applications contemplated by the inventors include,but are not limited to, those addressing pulmonary fibrosis, liverfibrosis, skin fibrosis, renal fibrosis, pancreas fibrosis, systemicsclerosis, cardiac fibrosis or macular degeneration.

The term “subject” includes living organisms in which a fibrotic diseasecan occur, or which are susceptible to such a condition. The term“subject” includes animals such as mammals or birds. Preferably, thesubject is a mammal. More preferably, the subject is a human. Even morepreferably, the subject is a human patient in need of treatment.

As used herein, “preventing” or “prevention” is intended to refer to atleast the reduction of likelihood of the risk of (or susceptibility to)acquiring a disease or disorder (i.e., causing at least one of theclinical symptoms of the disease not to develop in a patient that may beexposed to or predisposed to the disease but does not yet experience ordisplay symptoms of the disease). Biological and physiologicalparameters for identifying such patients are provided herein and arealso well known by physicians.

The terms “treatment” or “treating” of a subject includes theapplication or administration of a compound of the invention to asubject (or application or administration of a compound of the inventionto a cell or tissue from a subject) with the purpose of delaying,slowing, stabilizing, curing, healing, alleviating, relieving, altering,remedying, less worsening, ameliorating, improving, or affecting thedisease or condition, the symptom of the disease or condition, or therisk of (or susceptibility to) the disease or condition. The term“treating” refers to any indication of success in the treatment oramelioration of an injury, pathology or condition, including anyobjective or subjective parameter such as abatement; remission;lessening of the rate of worsening; lessening severity of the disease;stabilization, diminishing of symptoms or making the injury, pathologyor condition more tolerable to the subject; slowing in the rate ofdegeneration or decline; making the final point of degeneration lessdebilitating; or improving a subject's physical or mental well-being.

The present invention relates to methods, compounds, compositions andkit for preventing and/or treating a fibrotic disease.

The term “fibrotic disease” means any fibrosis or disease characterizedby an excess accumulation of extracellular matrix (primarily composed ofcollagen) and which results in loss of function when normal tissue isreplaced with scar tissue. The fibrotic disease includes, withoutlimitation, pulmonary fibrosis, liver fibrosis, skin fibrosis, renalfibrosis, pancreas fibrosis, systemic sclerosis, cardiac fibrosis andmacular degeneration.

The term “pulmonary fibrosis” or “lung fibrosis” means the formation ordevelopment of excess fibrous connective tissue (fibrosis) in the lungthereby resulting in the development of scarred (fibrotic) tissue. Moreprecisely, pulmonary fibrosis is a chronic disease that causes swellingand scarring of the alveoli and interstitial tissues of the lungs. Thescar tissue replaces healthy tissue and causes inflammation. Thischronic inflammation is, in turn, the prelude to fibrosis. This damageto the lung tissue causes stiffness of the lungs which subsequentlymakes breathing more and more difficult.

Pulmonary fibrosis is a complicated illness that can arise from manydifferent causes which include microscopic damage to the lungs inducedby inhalation of small particles (asbestos, ground stone, metal dust,particles present in cigarette smoke, silica dust, etc). Alternatively,pulmonary fibrosis may arise as a secondary effect of other diseases(autoimmune disease, viral or bacterial infections, etc). Certain drugssuch as cytotoxic agents (e.g. bleomycin, busulfan and methotrexate);antibiotics (e.g. nitrofurantoin, sulfasalazine); antiarrhitmics (e.g.amiodarone, tocainide); anti-inflammatory medications (e.g. gold,penicillamine); illicit drugs (e.g. crack cocaine, heroin); also cancause pulmonary fibrosis. However, when pulmonary fibrosis appearswithout a known cause, it is termed as “idiopathic” or idiopathicpulmonary fibrosis (IPF).

Pulmonary fibrotic disorders is thought to begin with acute injury tothe pulmonary parenchyma, leading to chronic interstitial inflammation,then to fibroblast activation and proliferation, and finally progressingto the common endpoint of pulmonary fibrosis and tissue destruction.Current research indicates that inflammation is less important in IPF,which appears to be primarily a disorder of fibroblast activation andproliferation in response to some as yet unknown trigger(s). Broadly,the manifestations of fibrotic lung disease can be grouped as follows:they may be chronic, insidious, and slowly progressive; they may besubacute, with a resolving, remitting, relapsing, or progressive course;and they may be acute, with a fulminant, progressive, remitting, orresolving course. Disorders with chronic, insidious, and slowlyprogressive courses are those that clinically resemble IPF and usuallyshare a common pathology (ie, UIP). Many of the connective-tissuediseases (e.g. rheumatoid arthritis; CREST syndrome (calcinosis cutis,Raynaud's syndrome, esophageal motility disorder, sclerodactyly, andtelangiectasia); syndrome/progressive systemic scleroderma; systemiclupus erythematosus; mixed connective-tissue disease; pneumoconioses(e.g. asbestosis, silicosis); chronic hypersensitivity pneumonitis; anddrug-related pulmonary fibrosis (e.g. due to bleomycin) generally fitinto this category. Development of clinically apparent lung diseasesrelated to occupational exposures (e.g. pneumoconiosis) generally occursmany years after the exposure. Radiation fibrosis often develops monthsto years after radiation exposure. A lag time of months or years canoccur between the use of pulmonary toxic medications and the developmentof fibrotic disease. The effect can be dose-dependent (e.g. bleomycin),although, in other cases, the relationship is less clear. Pulmonarymanifestations of connective-tissue disease may develop in advance of,coincident with, or many years after the onset of articular disease.Pulmonary sarcoidosis, although sometimes acute or subacute in onset, insome cases may present insidiously over time. Subacute presentationswith a variable course are typified by cryptogenic organizing pneumonia(COP). COP often develops weeks or months after the onset of a flulikeillness. The course is variable and may either spontaneously remit orprogress. The disorder is thought to be very responsive to steroidtherapy, although it may recur when steroids are withdrawn or tapered.In some cases, COP may progress to end-stage fibrotic lung disease.Disorders with an acute onset are typified by acute interstitialpneumonitis (AIP), which is an idiopathic form of severe lung injury.The histopathology is that of adult respiratory distress syndrome withdiffuse alveolar damage. Patients present either with no antecedenthistory of lung disease or as part of an accelerated phase of underlyinginterstitial disease. Most patients progress rapidly to respiratoryfailure. Some patients may improve with steroids or otherimmunosuppressive therapy.

The term “liver fibrosis” means the formation or development of excessfibrous connective tissue (fibrosis) in the liver thereby resulting inthe development of scarred (fibrotic) tissue. The scarred tissuereplaces healthy tissue by the process of fibrosis and leads tosubsequent cirrhosis of the liver and to hepatocellular carcinoma.

The term “skin fibrosis” or “dermal fibrosis” means the excessiveproliferation of epithelial cells or fibrous connective tissue(fibrosis) thereby resulting in the development of scarred (fibrotic)tissue. The scarred tissue replaces healthy tissue by the process offibrosis and may be the prelude of systemic scleroderma. Skin fibrosisis intended to cover the fibrosis of any skin tissue and epithelialcells including, without limitation, blood vessels and veins, internalcavity of an organ or a gland such as ducts of submandibular,gallbladder, thyroid follicles, sweat gland ducts, ovaries, kidney;epithelial cells of gingival, tongue, palate, nose, larynx, oesophagus,stomach, intestine, rectum, anus and vagina; derma, scar, skin andscalp. The compounds of the present invention are active for promotinghealing of wound and one or more of the following activities:

-   -   improving collagen organization and/or reducing wound        cellularity in said wound;    -   reducing collagen overproduction by fibroblast and epithelial        cells in said wound;    -   reducing epithelial mesenchymal transition in said wound;    -   reducing fibroblast migration and activation in said wound;    -   reducing and/or inhibiting dermal thickening in said wound;    -   reducing and/or inhibiting recruitment of inflammatory cells to        said wound.

In general, prophylactic and therapeutic uses comprise theadministration of a compound as described herein to a subject,preferably a human patient in need thereof. The compounds according tothe invention may be administered in combination with a therapeuticallyeffective amount of a second compound which can be comprised in the samepharmaceutical composition or in a second pharmaceutical composition.The second compound is advantageously an immunosuppressive drugincluding, but not limited to, cyclosporine, azathioprine,cyclophosphamide, or mycophenolate mofetil; an anti-inflammatory drugincluding, but not limited to, a corticosteroid (e.g. prednisone), acytokine including but not limited to, interferon-alpha, interferongamma, interleukine 12; a monoclonal antibody including but not limitedto CTGF, TGF-β, MCP-1, IL-4 and IL-13; a multiple receptor tyrosinekinase inhibitor including, but not limited to, Nintedanib and the JNK(kinase) inhibitor Tanzisertib (CC-930); an antioxidant such as, but notlimited to, N-acetylcysteine, pirfenidone, vitamin E, S-adenosylmethionine, or penicillamine; an enzyme inhibitor including, but notlimited, to Lysyloxidase-like-2 (LOXL2 enzyme); an integrin inhibitorsuch as, but not limited to, α_(v)β₆; a lipid receptor modulatorincluding, but not limited to, lysophosphatidic acid receptorantagonists; pirfenidone, or a thiazolindione.

A related aspect of the invention concerns pharmaceutical compositionsand kits which comprise one or more of the compounds of the inventiondescribed herein. As indicated herein above, the compounds of theinvention may be useful in preventing and/or treating a fibroticdisease.

A related aspect of the invention concerns the prophylactic andtherapeutic uses of a compound in related to a fibrotic disease.

Pulmonary fibrosis can lead to several severe complications. Because thefibrotic lungs have impaired oxygen intake capacity, low blood oxygenlevels (hypoxemia) can develop. Lack of oxygen can affect the entirebody. Another complication of pulmonary fibrosis is pulmonaryhypertension (high blood pressure in the arteries of the lungs). Scartissue in the lungs can make it more difficult for blood to flow throughthem. The increased pressure makes the heart work harder and leads to aweakened and enlarged heart, reducing its pumping efficiency andproducing heart failure. This is suspected when people develop fluidaccumulations in the abdomen, leg swelling, or prominent pulsations inneck veins.

Liver fibrosis can lead to severe malfunction of the liver and canresult in complete non-functioning of the liver.

Skin fibrosis can lead to hash mark, permanent cicatrix and scar causingsevere esthetic problems and stiffness of the skin following a skininjury from a surgery or an accident.

As used herein, the term “therapeutically effective amount” means theamount of compound that, when administered to a subject for treating orpreventing a particular disorder, disease or condition, is sufficient toeffect such treatment or prevention of that disorder, disease orcondition. Dosages and therapeutically effective amounts may vary forexample, depending upon a variety of factors including the activity ofthe specific agent employed, the age, body weight, general health,gender, and diet of the subject, the time of administration, the routeof administration, the rate of excretion, and any drug combination, ifapplicable, the effect which the practitioner desires the compound tohave upon the subject and the properties of the compounds (e.g.,bioavailability, stability, potency, toxicity, etc.), and the particulardisorder(s) the subject is suffering from. In addition, thetherapeutically effective amount that is administered intravenously maydepend on the subject's blood parameters e.g., lipid profile, insulinlevels, glycemia or liver metabolism. The therapeutically effectiveamount will also vary according to the severity of the disease state,organ function, or underlying disease or complications. Such appropriatedoses may be determined using any available assays including the assaysdescribed herein. When one or more of the compounds of the invention isto be administered to humans, a physician may for example, prescribe arelatively low dose at first, subsequently increasing the dose until anappropriate response is obtained. The dose for oral administration ofthe compounds according to the invention in human is between 1 to 50mg/kg, preferably 5 to 20 mg/kg, more preferably 5 to 15 mg/kg, alsomore preferably about 1 to 10 mg/kg in human. The dose of topicaladministration of the compounds of the present invention in human isbetween 0.01 to 10% (w/w), preferably 0.1 to 5% (w/w), and morepreferably 1 to 5%. The metabolism of a mouse eliminates any compoundfaster than human metabolism, such that for testing of a compound inmice, the dose may be multiplied 10 times to 20 times.

As used herein, the term “pharmaceutical composition” refers to thepresence of at least one compound according to the invention and apharmaceutically acceptable vehicle.

“Pharmaceutically acceptable vehicle” refers to a diluent, adjuvant,excipient, or carrier with which a compound is administered. The term“pharmaceutically acceptable” refers to drugs, medicaments, inertingredients etc., which are suitable for use in contact with the tissuesof humans and lower animals without undue toxicity, incompatibility,instability, irritation, allergic response, and the like, commensuratewith a reasonable benefit/risk ratio. It preferably refers to a compoundor composition that is approved or approvable by a regulatory agency ofthe Federal or State government or listed in the U.S. Pharmacopoeia orother generally recognized pharmacopoeia for use in animals and moreparticularly in humans. The pharmaceutically acceptable vehicle can be asolvent or dispersion medium containing, for example, water, ethanol,polyol (e.g. glycerol, propylene glycol, and liquid polyethyleneglycol), suitable mixtures thereof, and vegetable oils. Additionalexamples of pharmaceutically acceptable vehicles include, but are notlimited to: Water for Injection USP; aqueous vehicles such as, but notlimited to, Sodium Chloride Injection, Ringer's Injection, DextroseInjection, Dextrose and Sodium Chloride Injection, and Lactated Ringer'sInjection; water-miscible vehicles such as, but not limited to, ethylalcohol, polyethylene glycol, and polypropylene glycol; and non-aqueousvehicles such as, but not limited to, corn oil, cottonseed oil, peanutoil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.Prevention of the action of microorganisms can be achieved by additionof antibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In manycases, isotonic agents are included, for example, sugars, sodiumchloride, or polyalcohols such as mannitol and sorbitol, in thecomposition. Prolonged absorption of injectable compositions can bebrought about by including in the composition an agent which delaysabsorption, for example, aluminum monostearate or gelatin.

In some embodiments, the composition of the present invention comprisesan effective amount of a compound of the formula herein above.Particularly preferred is the sodium salt of 2-[3,5-dipentylphenyl]acetate.

In some embodiments, the invention pertains to pharmaceuticalcompositions for preventing and/or treating pulmonary fibrosis, liverfibrosis, skin fibrosis, renal fibrosis, pancreas fibrosis, systemicsclerosis, cardiac fibrosis or macular degeneration

The compounds of the invention may be formulated prior to administrationinto pharmaceutical compositions using available techniques andprocedures. For instance, the pharmaceutical compositions may beformulated in a manner suitable for administration by topical, oral,intravenous (iv), intramuscular (im), depo-im, subcutaneous (sc),depo-sc, sublingually, intranasal, intrathecal topical or rectal routes.

Preferably, the compound(s) of the invention can be orally administeredor topically administered. The formulations may conveniently bepresented in unit dosage form and may be prepared by any methods wellknown in the art of pharmacy. Methods of preparing these formulations orcompositions include the step of bringing into association a compound ofthe present invention with a pharmaceutically acceptable vehicle (e.g.,an inert diluent or an assimilable edible carrier) and, optionally, oneor more accessory ingredients. In general, the formulations are preparedby uniformly and intimately bringing into association a compound of thepresent invention with liquid carriers, or finely divided solidcarriers, or both, and then, if necessary, shaping the product. Theamount of the therapeutic agent in such therapeutically usefulcompositions is such that a suitable dosage will be obtained.

Formulations of the invention suitable for oral administration may be inthe form of capsules (e.g., hard or soft shell gelatin capsule),cachets, pills, tablets, lozenges, powders, granules, pellets, dragees,e.g., coated (e.g., enteric coated) or uncoated, or as a solution or asuspension in an aqueous or non-aqueous liquid, or as an oil-in-water orwater-in-oil liquid emulsion, or as an elixir or syrup, or as pastillesor as mouth washes and the like, each containing a predetermined amountof a compound of the present invention as an active ingredient. Acompound of the present invention may also be administered as a bolus,electuary or paste, or incorporated directly into the subject's diet.Moreover, in certain embodiments these pellets can be formulated to (a)provide for instant or rapid drug release (i.e., have no coating onthem); (b) be coated, e.g., to provide for sustained drug release overtime; or (c) be coated with an enteric coating for bettergastrointestinal tolerability. Coating may be achieved by conventionalmethods, typically with pH or time-dependent coatings, such that thecompound(s) of the invention is released in the vicinity of the desiredlocation, or at various times to extend the desired action. Such dosageforms typically include, but are not limited to, one or more ofcellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethyl cellulose phthalate, ethyl cellulose, waxes, and shellac.

In solid dosage forms for oral administration a compound of the presentinvention may be mixed with one or more pharmaceutically acceptablecarriers, such as sodium citrate or dicalcium phosphate, or any of thefollowing: fillers or extenders, such as starches, lactose, sucrose,glucose, mannitol, or silicic acid; binders, such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone,sucrose or acacia; humectants, such as glycerol; disintegrating agents,such as agar-agar, calcium carbonate, potato or tapioca starch, alginicacid, certain silicates, and sodium carbonate; solution retardingagents, such as paraffin; absorption accelerators, such as quaternaryammonium compounds; wetting agents, such as, for example, cetyl alcoholand glycerol monostearate; absorbents, such as kaolin and bentoniteclay; lubricants, such as talc, calcium stearate, magnesium stearate,solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof;and coloring agents. In the case of capsules, tablets and pills, thepharmaceutical compositions may also comprise buffering agents. Solidcompositions of a similar type may also be employed as fillers in softand hard-filled gelatin capsules using such excipients as lactose ormilk sugars, as well as high molecular weight polyethylene glycols andthe like.

Peroral compositions typically include liquid solutions, emulsions,suspensions, and the like. The pharmaceutically acceptable vehiclessuitable for preparation of such compositions are well known in the art.Typical components of carriers for syrups, elixirs, emulsions andsuspensions include ethanol, glycerol, propylene glycol, polyethyleneglycol, liquid sucrose, sorbitol and water. For a suspension, typicalsuspending agents include methyl cellulose, sodium carboxymethylcellulose, tragacanth, and sodium alginate; typical wetting agentsinclude lecithin and polysorbate 80; and typical preservatives includemethyl paraben and sodium benzoate. Peroral liquid compositions may alsocontain one or more components such as sweeteners, flavoring agents andcolorants disclosed above.

Pharmaceutical preparation suitable for injectable use may includesterile aqueous solutions (where water soluble) or dispersions andsterile powders for the extemporaneous preparation of sterile injectablesolutions or dispersions. In all cases, the composition must be sterileand must be fluid to the extent that easy syringability exists. It mustbe stable under the conditions of manufacture and storage and must bepreserved against the contaminating action of microorganisms such asbacteria and fungi. Sterile injectable solutions can be prepared byincorporating the therapeutic agent in the required amount in anappropriate solvent with one or a combination of ingredients enumeratedabove, as required, followed by filtered sterilization. Generally,dispersions are prepared by incorporating the therapeutic agent into asterile vehicle which contains a basic dispersion medium and therequired other ingredients from those enumerated above. In the case ofsterile powders for the preparation of sterile injectable solutions, themethods of preparation are vacuum drying and freeze-drying which yieldsa powder of the active ingredient (i.e., the therapeutic agent) plus anyadditional desired ingredient from a previously sterile-filteredsolution thereof.

Pharmaceutical formulations are also provided which are suitable foradministration as an aerosol, by inhalation. These formulations comprisea solution or suspension of the desired compound of any Formula hereinor a plurality of solid particles of such compound(s). For instance,metal salts of the compounds of this invention are expected to havephysical chemical properties amenable with the preparation of fineparticles of active pharmaceutical ingredient (API) for administrationby inhalation but not the free acid form of these compounds. The desiredformulation may be placed in a small chamber and nebulized. Nebulizationmay be accomplished by compressed air or by ultrasonic energy to form aplurality of liquid droplets or solid particles comprising the agents orsalts. The liquid droplets or solid particles should have a particlesize in the range of about 0.5 to about 5 microns. The solid particlescan be obtained by processing the solid agent of any Formula describedherein, or a salt thereof, in any appropriate manner known in the art,such as by micronization. The size of the solid particles or dropletswill be, for example, from about 1 to about 2 microns. In this respect,commercial nebulizers are available to achieve this purpose. Apharmaceutical formulation suitable for administration as an aerosol maybe in the form of a liquid, the formulation will comprise awater-soluble agent of any Formula described herein, or a salt thereof,in a carrier which comprises water. A surfactant may be present whichlowers the surface tension of the formulation sufficiently to result inthe formation of droplets within the desired size range when subjectedto nebulization.

The compositions of this invention may also be administered topically toa subject, e.g., by the direct laying on or spreading of the compositionon the epidermal or epithelial tissue of the subject, or transdermallyvia a “patch”. Such compositions include, for example, lotions, creams,solutions, gels, emulsions and solids. These topical compositions maycomprise an effective amount, usually about 0.01% to about 10% (w/w), orfrom about 0.1% to about 5% (w/w), or from about 1% to about 5% (w/w),of a compound of the invention. Suitable carriers for topicaladministration typically remain in place on the skin as a continuousfilm, and resist being removed by perspiration or immersion in water.Generally, the carrier is organic in nature and capable of havingdispersed or dissolved therein the therapeutic agent. The carrier mayinclude pharmaceutically acceptable emollients, emulsifiers, thickeningagents, solvents and the like. The carrier may include vernix. Topicalformulation includes one or more excipients such as, but not limited to,protectives, adsorbents, demulcents, emollients, preservatives,antioxidants, moisturizers, buffering agents, solubilizing agents,skin-penetration agents, and surfactants. Suitable protectives andadsorbents include, but are not limited to, dusting powders, zincsterate, collodion, dimethicone, silicones, zinc carbonate, aloe veragel and other aloe products, vitamin E oil, allatoin, glycerin,petrolatum, and zinc oxide. Suitable demulcents include, but are notlimited to, benzoin, hydroxypropyl cellulose, hydroxypropylmethylcellulose, and polyvinyl alcohol. Suitable emollients include, butare not limited to, animal and vegetable fats and oils, myristylalcohol, alum, and aluminum acetate. Suitable preservatives include, butare not limited to, quaternary ammonium compounds, such as benzalkoniumchloride, benzethonium chloride, cetrimide, dequalinium chloride, andcetylpyridinium chloride; mercurial agents, such as phenylmercuricnitrate, phenylmercuric acetate, and thimerosal; alcoholic agents, forexample, chlorobutanol, phenylethyl alcohol, and benzyl alcohol;antibacterial esters, for example, esters of parahydroxybenzoic acid;and other anti-microbial agents such as chlorhexidine, chlorocresol,benzoic acid and polymyxin. Suitable antioxidants include, but are notlimited to, ascorbic acid and its esters, sodium bisulfite, butylatedhydroxytoluene, butylated hydroxyanisole, tocopherols, and chelatingagents like EDTA and citric acid. Suitable moisturizers include, but arenot limited to, glycerin, sorbitol, polyethylene glycols, urea, andpropylene glycol. Suitable buffering agents for use with the inventioninclude, but are not limited to, acetate buffers, citrate buffers,phosphate buffers, lactic acid buffers, and borate buffers. Suitablesolubilizing agents include, but are not limited to, quaternary ammoniumchlorides, cyclodextrins, benzyl benzoate, lecithin, and polysorbates.Suitable skin-penetration agents include, but are not limited to, ethylalcohol, isopropyl alcohol, octylphenylpolyethylene glycol, oleic acid,polyethylene glycol 400, propylene glycol, N-decylmethylsulfoxide, fattyacid esters (e.g., isopropyl myristate, methyl laurate, glycerolmonooleate, and propylene glycol monooleate); and N-methylpyrrolidone.

Other compositions useful for attaining systemic delivery of the subjectagents may include sublingual, buccal and nasal dosage forms. Suchcompositions typically comprise one or more of soluble filler substancessuch as sucrose, sorbitol and mannitol; and binders such as acacia,microcrystalline cellulose, carboxymethyl cellulose and hydroxypropylmethyl cellulose. Glidants, lubricants, sweeteners, colorants,antioxidants and flavoring agents disclosed above may also be included.

The compound according to the present invention may also be administeredparenterally, intraperitoneally, intraspinally, or intracerebrally. Forsuch compositions, the compound of the invention can be prepared inglycerol, liquid polyethylene glycols, and mixtures thereof and in oils.Under ordinary conditions of storage and use, this preparation maycontain a preservative to prevent the growth of microorganisms.

For the method of prevention/slowing progression/treatment of a fibroticdisease, the method of the present invention may also includeco-administration of the at least one compound according to theinvention, or a pharmaceutically acceptable salt thereof together withthe administration of another therapeutically effective agent for theprevention and/or slowing the progression and/or treatment of a fibroticdisease. Accordingly, the invention also relates to a method forpreventing, reducing or eliminating a symptom or complication of any oneof the above mentioned disease or condition. The method comprises theadministration of a first pharmaceutical composition comprising at leastone compound of the invention and a second pharmaceutical compositioncomprising one or more additional active ingredients to a subject inneed thereof, wherein all active ingredients are administered in anamount sufficient to inhibit, reduce, or eliminate one or more symptomsor complications of the disease or condition to be treated. In oneaspect, the administration of the first and second pharmaceuticalcomposition is temporally spaced apart by at least about two minutes.Preferably the first agent is a compound of formula I. The second agentmay be selected from the list of compounds given herein above.

The present invention is not intended to be limited to the embodimentsshown herein but is to be accorded the widest scope consistent with theprinciples and novel features disclosed herein.

The singular forms “a”, “an” and “the” include corresponding pluralreferences unless the context clearly dictates otherwise.

Unless otherwise indicated, all numbers expressing quantities ofingredients, reaction conditions, concentrations, properties, and soforth used in the specification and claims are to be understood as beingmodified in all instances by the term “about.” At the very least, eachnumerical parameter should at least be construed in light of the numberof reported significant digits and by applying ordinary roundingtechniques. Accordingly, unless indicated to the contrary, the numericalparameters set forth in the present specification and attached claimsare approximations that may vary depending upon the properties sought tobe obtained. Notwithstanding that the numerical ranges and parameterssetting forth the broad scope of the embodiments are approximations, thenumerical values set forth in the specific examples are reported asprecisely as possible. Any numerical value, however, inherently containcertain errors resulting from variations in experiments, testingmeasurements, statistical analyses and such.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, numerous equivalents to thespecific procedures, embodiments, claims, and examples described herein.Such equivalents are considered to be within the scope of this inventionand covered by the claims appended hereto. The invention is furtherillustrated by the following examples, which should not be construed asfurther

EXAMPLES

The examples set forth herein below provide exemplary methods for thepreparation of certain representative compounds encompassed by FormulaI. Some Examples provide exemplary uses of certain representativecompounds of the invention. Also provided are exemplary methods forassaying the compounds of the invention for efficacy.

The examples set forth herein below provide exemplary methods for thepreparation of certain representative compounds encompassed by generalFormula I. Some Examples provide exemplary uses of certainrepresentative compounds of the invention. Also provided are exemplarymethods for assaying the compounds of the invention for in vitro and invivo efficacy.

Instrumentation:

All HPLC chromatograms and mass spectra were recorded on an HP 1100LC-MS Agilent instrument using an analytical C18 column (250×4.6 mm, 5microns) with a gradient over 3 min of 50-99% CH3CN-H2O with 0.01% TFAas the eluant followed by isocratic over 3 min and a flow of 2 mL/min.

Example 1 Experimental Procedure for the Preparation of Sodium2-[3,5-Dipentylphenyl] Acetate (Compound 1)

Step 1:

A suspension of methyl 2-[3,5-dihydroxyphenyl]acetate (1.00 g, 5.49mmol) and N-phenyl-bis(trifluoromethylsulfonyl)imide (4.31 g, 12.1 mmol)in dichloromethane (20 ml), at 0° C. under nitrogen, was treated withtriethylamine (1.68 ml, 12.1 mmol). A clear solution formed. Thereaction was then stirred under nitrogen at 0° C. for 2 h, and at roomtemperature for 21 h. The reaction was diluted with ethyl acetate (100ml), and the solution was washed with 0.5M aqueous sodium hydroxide(2×100 ml), and with saturated aqueous sodium chloride (75 ml); thendried over sodium sulphate; filtered and evaporated in vacuo to give thecrude product. Purification on a Biotage™ 40iM column (silica), elutingwith ethyl acetate/hexane 0:1 to 1:9, gave methyl2-[3,5-bis(trifluoromethylsulfonyloxy)phenyl]acetate (2.23 g, 91%) aspale oil. ¹H NMR (400 MHz, CDCl3): δ 7.32 (d, J=2.2 Hz, 2H), 7.18 (dd,J=2.2, 2.2 Hz, 1H), 3.72 (s, 5H); 19F NMR (377 MHz, CDCl3): δ −73.20 (s,3F); ¹³C NMR (101 MHz, CDCl3): δ 170.05, 149.48, 139.01, 122.95, 118.87(q, JCF=320.5 Hz), 114.42, 52.62, 40.29.

Step 2:

A solution of the aryl bis(triflate) (2.23 g, 4.99 mmol) and(E)-1-penten-1-ylboronic acid pinacol ester (2.45 g, 12.5 mmol) in1,2-dimethoxyethane (25 ml) was treated with a solution of sodiumcarbonate (1.59 g, 15.0 mmol) in water (8 ml). The solution wasdeoxygenated with nitrogen, and was then treated withTetrakis(triphenylphosphine) palladium (0.58 g, 0.50 mmol). The mixturewas heated at 90° C., in a sealed tube for 17 h. The reaction was cooledto room temperature and was partitioned between ethyl acetate (200 ml)and 1M aqueous hydrochloric acid (150 ml). The organic phase was washedwith 5% aqueous sodium bicarbonate (150 ml), and with saturated aqueoussodium chloride (150 ml); then dried over sodium sulphate; filtered, andevaporated in vacuo to give the crude product. Purification on aBiotage™ 40iL column (silica), eluting with ethyl acetate/hexane 0:1 to3:97, gave methyl 2-[3,5-di[(E)-1-pent-1-enyl]phenyl] acetate as aninseparable 10:4 mixture with excess (E)-1-penten-1-ylboronic acidpinacol ester (1.12 g, 61%). ¹H NMR (400 MHz, CDCl3): δ 7.21 (s, 1H),7.10 (d, J=1.3 Hz, 2H), 6.34 (d, J=15.8 Hz, 1H), 6.22 (dd, J=15.8, 6.7Hz, 1H), 3.65 (s, 3H), 3.55 (s, 2H), 2.18 (tdd, J=6.8, 6.8, 1.0 Hz, 2H),1.49 (qt, J=7.4, 7.2 Hz, 2H), 0.96 (t, J=7.4 Hz, 3H); ¹³C NMR (101 MHz,CDCl3): δ 172.04, 138.59, 134.47, 131.34, 129.97, 125.57, 122.75, 52.07,41.32, 35.39, 22.77, 13.97.

Step 3:

A solution of the unsaturated compound (1.12 g, 78.5% w/w, 3.07 mmol) inethyl acetate (1 ml) and methanol (1 ml) was treated with palladium oncarbon (10% w/w Pd; 0.12 g). The mixture was degassed with hydrogen, andwas stirred under 1 atm. of hydrogen at room temperature for 22 h. Thereaction was filtered, and evaporated in vacuo to give methyl2-[3,5-dipentylphenyl] acetate as an inseparable 10:4 mixture withpentylboronic acid pinacol ester (0.86 g, 76%). ¹H NMR (400 MHz, CDCl3):δ 6.93 (s, 3H), 3.70 (s, 3H), 3.59 (s, 2H), 2.58 (t, J=7.9 Hz, 2H),1.58-1.66 (m, 2H), 1.32-1.38 (m, 4H), 0.91 (t, J=6.8 Hz, 3H).

Step 4:

A solution of the methyl ester (0.86 g, 79% w/w, 2.34 mmol) inacetonitrile (24 ml) was treated with a solution of lithium hydroxide(0.28 g, 11.7 mmol) in water (6 ml), and the reaction was stirred atroom temperature for 22 h. The reaction was quenched with 1M aqueoushydrochloric acid (55 ml), and then extracted with ethyl acetate (100ml). The organic extract was washed with saturated aqueous sodiumchloride (50 ml); then dried over sodium sulphate; filtered, andevaporated in vacuo to give the crude product. Purification on aSiliaSep silicon oxide column, eluting with ethyl acetate/hexane 0:1 to1:4, gave 2-[3,5-dipentyl]phenyl] acetic acid as a colorless oil (0.55g, 84%). ¹H NMR (400 MHz, CDCl3): δ 6.99 (s, 3H), 3.65 (s, 2H), 2.63 (t,J=7.8 Hz, 2H), 1.64-71 (m, 2H), 1.36-1.44 (m, 4H), 0.97 (t, J=6.9 Hz,3H); ¹³C NMR (101 MHz, CDCl3): δ 178.96, 143.55, 133.21, 127.93, 127.06,41.47, 36.13, 31.94, 31.47, 22.86, 14.34.

Step 5:

A solution of the acid (0.48 g, 1.75 mmol) in ethanol (12 ml) wastreated with a solution of sodium bicarbonate (0.15 g, 1.75 mmol) inwater (3 ml), and the reaction was stirred at room temperature for 3 d.Ethanol was evaporated in vacuo, and the residual aqueous syrup wasdiluted with water (50 ml), filtered (PES, 0.2 μm), and lyophilised togive sodium 2-[3,5-dipentylphenyl] acetate as a white solid (0.52 g,quantitative). mp 225-230° C.; ¹H NMR (400 MHz, CD3OD+D2O): δ 6.92 (s,2H), 6.76 (s, 1H), 3.41 (s, 2H), 2.50 (t, J=7.5 Hz, 2H), 1.52-1.59 (m,2H), 1.23-1.33 (m, 4H), 0.85 (t, J=6.9 Hz, 3H); ¹³C NMR (101 MHz,CD3OD+D2O): δ 179.99, 142.66, 137.63, 126.66, 126.16, 45.11, 35.61,31.36, 31.19, 22.41, 13.47; LRMS (ESI): m/z 277.5 (w, [M−Na++2H+]),231.1 (100%, tropylium ion from loss of carboxy group); HPLC: 3.0 min.

Compound 2, Sodium Salt of 2-(3,5-Dihexylphenyl)acetic Acid

The above compound was prepared from (E)-hex-1-enylboronic acid pinacolester as for compound 1. White solid; ¹H NMR (400 MHz, CD₃OD): δ 6.96(s, 2H), 6.79 (s, 1H), 3.43 (s, 2H), 2.54 (d, J=7.7 Hz, 4H), 1.55-1.63(m, 4H), 1.28-1.36 (m, 12H), 0.89 (t, J=6.8 Hz, 6H); ¹³C NMR (101 MHz,CD₃OD): δ 179.68, 142.38, 137.82, 126.55, 126.07, 45.30, 35.87, 31.83,31.67, 29.02, 22.61, 13.42; LRMS (ESI): m/z 322.0 (100%, M−Na⁺+H⁺+NH₄ ⁺)and 259.0 (35%, M−CO₂Na); UPLC (System A): 8.9 min. UPLC System A:Mobile phase A=10 mM aqueous ammonium bicarbonate; mobile phaseB=acetonitrile; solid phase=HSS T3 column; gradient=5-100% B in A over10 minutes.

Compound 3, Sodium Salt of 2-(2-Hydroxy-3,5-dipentylphenyl)acetic Acid

Step 1

A solution of 2,4-dibromo-6-(bromomethyl)phenol (3.5 g, 10.0 mmol) inacetonitrile (17 ml) was treated with a solution of sodium cyanide (2.5g, 50.0 mmol) and the reaction was heated at 100° C. under reflux for 1h. The reaction mixture cooled to room temperature and was poured intowater (100 ml). The pH was adjusted from 10 to 8 with 1M aqueoushydrochloric acid, and the mixture was extracted with ethyl acetate(3×250 ml). Combined extracts were washed with 1M aqueous hydrochloricacid (250 ml) and with saturated aqueous sodium chloride (250 ml); driedover sodium sulfate; filtered and evaporated in vacuo to give the crudeproduct. Extraction with acetone; filtration; and evaporation in vacuogave 2-(3,5-dibromo-2-hydroxyphenyl)acetonitrile (2.6 g, 90%). ¹H NMR(400 MHz, d₆-acetone): δ 8.75 (br s, 1H), 7.69 (d, J=2.3 Hz, 1H), 7.54(d, J=2.3 Hz, 1H), 3.92 (s, 2H); ¹³C NMR (101 MHz, d₆-acetone): δ151.31, 134.51, 131.92, 122.80, 117.43, 111.89, 111.53, 18.70.

Step 2

2-(3,5-Dibromo-2-hydroxyphenyl)acetonitrile (2.6 g, 9.0 mmol) wastreated with a mixture of sulfuric acid (2.5 ml), acetic acid (2.5 ml)and water (2.5 ml), and the reaction was heated at 125° C. under refluxfor 2 h. The reaction mixture was cooled to room temperature and waspoured into a mixture of ice (50 ml) and water (50 ml), and was thenstirred until the ice had melted. The mixture was extracted with ethylacetate (250 ml); and the extract was then washed with water (100 ml)and with saturated aqueous sodium chloride (100 ml); dried over sodiumsulfate; filtered and evaporated in vacuo to give the crude2-(3,5-dibromo-2-hydroxyphenyl)acetic acid (3.1 g). This material wasused directly in the next step without further purification orcharacterization.

Step 3

A solution of crude 2-(3,5-dibromo-2-hydroxyphenyl)acetic acid (3.1 g,9.0 mmol) in methanol (17 ml) was treated with sulfuric acid (0.43 ml,8.1 mmol) and the reaction was stirred at ambient temperature for 16 h.Methanol was evaporated in vacuo, and the residue was dissolved in ethylacetate (270 ml). The solution was washed with water (2×200 ml) and withsaturated aqueous sodium chloride (130 ml); dried over sodium sulfate;filtered and evaporated in vacuo to give the crude product. Purificationon a Biotage™ SP1 system (120 g silica cartridge), eluting with 0-20%ethyl acetate in hexanes, gave methyl2-(3,5-dibromo-2-hydroxyphenyl)acetate (1.4 g, 49%). ¹H NMR (400 MHz,CDCl₃): δ 7.52 (d, J=2.2 Hz, 1H), 7.23 (d, J=2.2 Hz, 1H), 6.42 (br s,1H), 3.72 (s, 3H), 3.65 (s, 2H); ¹³C NMR (101 MHz, CDCl₃): δ 172.06,150.60, 133.74, 133.50, 123.94, 112.62, 111.77, 52.78, 36.61.

Step 4

A solution of methyl 2-(3,5-dibromo-2-hydroxyphenyl)acetate (0.5 g, 1.54mmol) in acetone (5 ml) was treated with potassium carbonate (0.26 g,1.86 mmol), potassium iodide (0.05 g, 0.32 mmol) and benzyl bromide(0.20 ml, 1.7 mmol), and the reaction was stirred at room temperaturefor 1 h. Acetone was evaporated in vacuo, and the residue waspartitioned between ethyl acetate (50 ml) and 1M aqueous hydrochloricacid (50 ml). The organic phase was washed with saturated aqueous sodiumchloride (50 ml); dried over sodium sulfate; filtered and evaporated invacuo to give the crude product. Purification on a Biotage™ SP1 system(40 g silica cartridge), eluting with 0-10% ethyl acetate in hexanes,gave methyl 2-(2-(benzyloxy)-3,5-dibromophenyl)acetate (0.6 g, 95%). ¹HNMR (400 MHz, CDCl₃): δ 7.67 (d, J=2.4 Hz, 1H), 7.48-7.51 (m, 2H), 7.37(d, J=2.4 Hz, 1H), 7.34-7.43 (m, 3H), 4.99 (s, 2H), 3.66 (s, 3H), 3.60(s, 2H); ¹³C NMR (101 MHz, CDCl₃): δ 171.26, 153.79, 136.56, 135.38,133.57, 132.04, 128.82, 128.64, 128.52, 118.69, 117.56, 75.53, 52.50,35.86.

Step 5

Methyl 2-(2-(benzyloxy)-3,5-dibromophenyl)acetate (0.3 g, 0.73 mmol) and(E)-pent-1-enylboronic acid pinacol ester (0.4 g, 1.79 mmol) werecoupled as for Compound I, step 2, to give methyl2-(2-(benzyloxy)-3,5-di((E)-pent-1-enyl)phenyl)acetate (0.21 mg, 72%).¹H NMR (400 MHz, CDCl₃): δ 7.50 (d, J=7.2 Hz, 2H), 7.44 (dd, J=7.2, 7.2Hz, 2H), 7.43 (d, J=2.1 Hz, 1H), 7.38 (dd, J=7.2, 7.2 Hz, 1H), 7.18 (d,J=2.1 Hz, 1H), 6.72 (d, J=15.8 Hz, 1H), 6.39 (d, J=15.8 Hz, 1H), 6.32(dt, J=15.8, 7.0 Hz, 1H), 6.22 (dt, J=15.8, 6.8 Hz, 1H), 4.87 (s, 2H),3.69 (s, 3H), 3.67 (s, 2H), 2.20-2.29 (m, 4H), 1.50-1.60 (m, 4H), 1.01(t, J=7.3 Hz, 3H), 1.00 (t, J=7.4 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃): δ172.49, 153.59, 137.58, 134.35, 132.91, 131.91, 130.84, 129.53, 128.78,128.32, 128.30, 128.24, 127.26, 125.21, 123.89, 75.89, 52.21, 35.94,35.74, 35.42, 22.87, 22.77, 14.07, 14.06.

Step 6

Methyl 2-(2-(benzyloxy)-3,5-di((E)-pent-1-enyl)phenyl)acetate (0.2 g,0.53 mmol) was hydrogenated as for Compound I, step 3, to give methyl2-(2-hydroxy-3,5-dipentylphenyl)acetate (0.12 g, 73%). ¹H NMR (400 MHz,CDCl₃): δ 7.37 (s, 1H), 6.92 (d, J=2.1 Hz, 2H), 6.77 (d, J=2.1 Hz, 1H),3.76 (s, 3H), 3.67 (s, 2H), 2.65 (t, J=7.8 Hz, 2H), 2.51 (t, J=7.8 Hz,2H), 1.58-1.66 (m, 4H), 1.31-1.41 (m, 8H), 0.93 (t, J=7.0 Hz, 3H), 0.92(t, J=6.9 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃): δ 175.01, 151.27, 135.14,131.48, 129.92, 128.52, 120.30, 52.95, 38.35, 35.34, 32.15, 31.86,31.74, 30.61, 30.03, 22.87, 22.83, 14.34, 14.31.

Step 7

Methyl 2-(2-hydroxy-3,5-dipentylphenyl)acetate (0.2 g, 0.53 mmol) washydrolysed as for Compound I, step 4, to give the crude product mixedwith lactonised material. A small portion was purified on a Biotage™ SP1system (120 g silica cartridge), eluting with 0-100% ethyl acetate inhexanes, to give 2-(2-hydroxy-3,5-dipentylphenyl)acetic acid (13.5 mg).¹H NMR (400 MHz, CDCl₃): δ 10.5 (br s, 1H), 6.89 (d, J=2.2 Hz, 1H), 6.78(d, J=2.2 Hz, 1H), 6.32 (br s, 1H), 3.66 (s, 2H), 2.58 (t, J=7.9 Hz,2H), 2.48 (t, J=7.8 Hz, 2H), 1.52-1.63 (m, 4H), 1.26-1.37 (m, 8H), 0.90(t, J=7.0 Hz, 3H), 0.88 (t, J=6.8 Hz, 3H).

Step 8

2-(2-Hydroxy-3,5-dipentylphenyl)acetic acid (13.5 mg, 0.046 mmol) wasconverted to the sodium salt as for Compound I, step 5 to give sodium2-(2-hydroxy-3,5-dipentylphenyl)acetate (11 mg, 77%). ¹H NMR (400 MHz,CD₃OD): δ 6.72 (d, J=2.0 Hz, 1H), 6.69 (d, J=2.0 Hz, 1H), 3.46 (s, 2H),2.56 (t, J=7.6 Hz, 2H), 2.44 (t, J=7.6 Hz, 2H), 1.50-1.61 (m, 4H),1.25-1.37 (m, 8H), 0.90 (t, J=6.8 Hz, 3H), 0.88 (t, J=7.0 Hz, 3H); ¹³CNMR (101 MHz, CD₃OD): δ 180.33, 151.94, 133.47, 130.37, 128.21, 127.81,123.99, 42.90, 34.97, 31.81, 31.60, 31.40, 30.25, 29.88, 22.51, 22.45,13.29, 13.24; LRMS (ESI negative): m/z 291.2 (100%, M−Na⁺); UPLC (SystemB): 7.7 min. UPLC System B: Mobile phase A=0.1% aqueous formic acid;mobile phase B=0.1% formic acid in acetonitrile; solid phase=HSS T3column; gradient=5-100% B in A over 10 minutes.

Compound 4, Sodium Salt of 2-(3,5-Dihexyl-2-hydroxyphenyl)acetic Acid

The above compound was prepared as for Compound 3, using(E)-hex-1-enylboronic acid pinacol ester. ¹H NMR (400 MHz, CD₃OD): δ6.72 (d, J=2.0 Hz, 1H), 6.69 (d, J=2.0 Hz, 1H), 3.46 (s, 2H), 2.56 (t,J=7.6 Hz, 2H), 2.44 (t, J=7.5 Hz, 2H), 1.50-1.60 (m, 4H), 1.27-1.37 (m,12H), 0.89 (t, J=6.6 Hz, 3H), 0.88 (t, J=6.80 Hz, 3H); LRMS (ESInegative): m/z 319 (100%, M−Na⁺); UPLC (System B): 8.7 min. ULC SystemB: Mobile phase A=0.1% aqueous formic acid; mobile phase B=0.1% formicacid in acetonitrile; solid phase=HSS T3 column; gradient=5-100% B in Aover 10 minutes.

Compound 5, Sodium Salt of 2-(4-Hydroxy-3,5-dipentylphenyl)acetic Acid

The above compound was prepared as for Compound 3 from2-(3,5-dibromo-4-hydroxyphenyl)acetic acid. ¹H NMR (400 MHz, CD₃OD): δ6.87 (s, 2H), 3.33 (s, 2H), 2.55 (t, J=7.7 Hz, 4H), 1.53-1.61 (m, 4H),1.31-1.37 (m, 8H), 0.90 (t, J=7.0 Hz, 6H); LRMS (ESI negative): m/z291.1 (100%, M−Na⁺); UPLC (System B): 6.8 min. UPLC System B: Mobilephase A=0.1% aqueous formic acid; mobile phase B=0.1% formic acid inacetonitrile; solid phase=HSS T3 column; gradient=5-100% Bin A over 10minutes.

Compound 6, Sodium Salt of 2-(3,5-Dihexyl-4-hydroxyphenyl)acetic Acid

The above compound was prepared as for Compound 3, from2-(3,5-dibromo-4-hydroxyphenyl)acetic acid, and (E)-hex-1-enylboronicacid pinacol ester. ¹H NMR (400 MHz, CD₃OD): δ 6.72 (d, J=2.0 Hz, 1H),6.69 (d, J=2.0 Hz, 1H), 3.46 (s, 2H), 2.56 (t, J=7.6 Hz, 2H), 2.44 (t,J=7.5 Hz, 2H), 1.50-1.60 (m, 4H), 1.27-1.37 (m, 12H), 0.89 (t, J=6.6 Hz,3H), 0.88 (t, J=6.8 Hz, 3H); LRMS (ESI negative): m/z 319.1 (100%,M−Na⁺); UPLC (System B): 7.6 min. UPLC System B: Mobile phase A=0.1%aqueous formic acid; mobile phase B=0.1% formic acid in acetonitrile;solid phase=HSS T3 column; gradient=5-100% B in A over 10 minutes.

Compound 7, Sodium Salt of 2-(4-Fluoro-3,5-dihexylphenyl)acetic Acid

The above compound was prepared as for Compound 3, starting from3,5-dibromo-4-fluorobenzyl bromide and (E)-hex-1-enylboronic acidpinacol ester. 3,5-Dibromo-4-fluorobenzyl bromide was prepared bybromination of 3,5-dibromo-4-fluorotoluene with N-bromosuccinimide andazobisisobutyronitrile in acetonitrile at 80° C. ¹H NMR (400 MHz,CD₃OD): δ 6.98 (d, J_(HF)=7.0 Hz, 2H), 3.38 (s, 2H), 2.57 (t, J=7.7 Hz,4H), 1.54-1.61 (m, 4H), 1.28-1.37 (m, 12H), 0.89 (t, J=6.7 Hz, 6H); ¹⁹FNMR (377 MHz, CD₃OD): δ −132.17 (d, J_(HF)=6.6 Hz, 1F); ¹³C NMR (101MHz, CD₃OD): δ 179.44, 158.11 (d, J_(CF)=239.8 Hz), 133.26 (d,J_(CF)=3.8 Hz), 128.73 (d, J_(CF)=5.4 Hz), 128.56 (d, J_(CF)=16.9 Hz),44.52, 31.69, 30.35 (d, J_(CF)=1.5 Hz), 28.98, 28.97 (d, J_(CF)=3.1 Hz),22.51, 13.29; LRMS (ESI negative): m/z 321.0 (100%, M−Na⁺); UPLC (SystemB): 9.2 min. UPLC System B: Mobile phase A=0.1% aqueous formic acid;mobile phase B=0.1% formic acid in acetonitrile; solid phase=HSS T3column; gradient=5-100% B in A over 10 minutes.

Compound 8, Sodium Salt of 2-(4-Fluoro-3,5-dipentylphenyl)acetic Acid

The above compound was prepared as for Compound 3, starting from3,5-dibromo-4-fluorobenzyl bromide. ¹H NMR (400 MHz, CD₃OD): δ 6.98 (d,J_(HF)=6.8 Hz, 2H), 3.37 (s, 2H), 2.57 (t, J=7.6 Hz, 4H), 1.54-1.62 (m,4H), 1.28-1.37 (m, 8H), 0.90 (t, J=7.0 Hz, 6H); ¹⁹F NMR (377 MHz,CD₃OD): δ −132.34 (d, J_(HF)=6.6 Hz, 1F); ¹³C NMR (101 MHz, CD₃OD): δ179.41, 158.10 (d, J_(CF)=239.8 Hz), 133.26 (d, J_(CF)=3.8 Hz), 128.72(d, J_(CF)=4.6 Hz), 128.56 (d, J_(CF)=16.9 Hz), 44.51, 31.54, 30.07,28.92 (d, J_(CF)=3.1 Hz), 22.38, 13.22; LRMS (ESI negative): m/z 293.0(100%, M−Na⁺); UPLC (System B): 8.4 min. UPLC System B: Mobile phaseA=0.1% aqueous formic acid; mobile phase B=0.1% formic acid inacetonitrile; solid phase=HSS T3 column; gradient=5-100% B in A over 10minutes.

Example 2 Antifibrotic Effect of Compounds of the Present Invention onthe Fibrotic Markers α-SMA and Collagen 1 in TGF-β Induced Fibroblastand Epithelial Cells

Fibrosis is a chronic and progressive process characterized by anexcessive accumulation of extracellular matrix (ECM) leading tostiffening and/or scarring of the involved tissue. It develops throughcomplex cell, extracellular matrix, cytokine and growth factorinteractions. Distinct cell types are involved such as residentmesenchymal cells (fibroblasts and myofibroblasts) and ECM-producingcells derived from epithelial and endothelial cells (through a processtermed epithelial- and endothelial-mesenchymal transition), local orbone marrow-derived stem cells (fibrocytes). Myofibroblasts has longbeen regarded as a major cell type involved in normal wound healing, andas the key effector cell in fibrogenesis. They are highly synthetic forcollagen and other ECM components, and are characterized by the de novoexpression of α-smooth muscle actin (α-SMA) (reviewed in Scotton C. J.and Chambers R. C., 2007). The presence of myofibroblasts in fibroticlesions in animal models of fibrosis correlates with the development ofactive fibrosis, and their persistence and localization to fibrotic fociin human disease is associated with disease progression (Kuhn C. andMcDonald J. A., 1991, and Zhang et al., 1994). Myofibroblasts alsoexhibit an enhanced migratory phenotype (Suganuma et al. 1995) and arecapable of releasing numerous pro-fibrotic mediators.

In fibroblast, analysis was undertaken to determine the effect ofpreferred compounds of the present invention on TGF-β-induced α-SMA(marker of fibrosis) mRNA expression on normal rat kidney fibroblast(NRK-49F). NRK-49F were treated with TGF-β at a concentration of 10ng/ml and became activated (myofibroblast) and expressed α-SMA.Expression of the profibrotic marker α-SMA was determined byquantitative real-time PCR. As shown in Table 2, the compounds of theinvention inhibit the expression of αA in TGF-β-induced NRK-49F cells.

TABLE 2 Inhibition of α-SMA mRNA expression by compounds in TGF-βinduced NRK-49F cells α-SMA expression in NRK-49F % of inhibitionCompound Structure [mM] 1

94% [0.01] 2

89% [0.006] 3

100% [0.0125] 5

41% [0.025]

The role of EMT during tissue injury leading to organ fibrosis(deposition of collagens, elastin, tenacin, and other matrix molecules)is becoming increasingly clear. A great bulk of such evidence exists forEMT associated with progressive kidney diseases, lung, skin, heart andliver. For example, in kidney, emerging evidence suggests that renaltubular epithelial cells can undergo epithelial to mesenchymaltransition (EMT) to become matrix-producing fibroblasts under pathologicconditions (Strutz F., Müller G. A., 2000; and Yang J., Liu Y., 2001).This phenotypic conversion not only illustrates the remarkableplasticity of mature, differentiated kidney epithelial cells, but isalso fundamentally implicated in the pathogenesis of a wide range ofchronic renal diseases (Iwano M. et al., 2002; Yang J. et al., 2002;Zeisberg M. et al., 2001; and Yang J., Liu Y., 2002). Recent studiesprovide compelling evidence that a large proportion of the interstitialfibroblasts in fibrotic kidneys originate from tubular epithelial cellsvia EMT (Iwano M. et al., 2002). Likewise, selective blockade of tubularEMT, due to preservation of tubular basement membrane integrity intPA−/− mice, protects the kidney from developing fibrotic lesions afterobstructive injury (Yang J. et al., 2002). These observations underscorethe crucial importance of tubular EMT in the onset and progression ofchronic renal fibrosis that eventually results in end-stage renalfailure. Several factors have been suggested as potential initiators ofEMT in different in vitro and in vivo models (Yang J, Liu Y., 2001;Kalluri R., Neilson E. G., 2003; Okada H. et al, 1997; Fan J. M. et al,2001; Strutz F. et al., 2002; Ha H., Lee H. B., 2003; Lan H. Y., 2003;Lee J. M. et al., 2006; and Zavadil J., Böttinger E. R, 2005). With theexception of CTGF, each of these mediators requires the induction ofTGF-β to complete the process of EMT (Yang J., Liu Y., 2001; Liu Y.,2004; and Lan H. Y., 2003).

In epithelial cells, analysis was undertaken to determine the effect ofcompounds of the invention on TGF-β-induced collagen 1 (marker offibrosis) on human proximal tubule epithelial cells (HK-2). HK-2 cellsare immortalized proximal tubule epithelial cells, from human kidney,which were treated with TGF-β at a concentration of 10 ng/mL Expressionof the profibrotic marker collagen 1 was determined by quantitativereal-time PCR. As shown in Table 3, Compound 1 and 2 inhibits theexpression of collagen in TGF-6-induced HK-2 cells.

TABLE 3 Inhibition of collagen mRNA expression in TGF-β induced HK-2epithelial cells Collagen expression in HK-2 cells % of inhibitionCompound Structure [mM] 1

100% [0.02] 2

100% [0.008]

Example 3 Antifibrotic Effect of Compounds of the Invention on SkinFibrosis

The effect of Compound 1 of the invention on skin fibrosis was alsostudied using normal human dermal fibroblasts (NHDF).

In vitro analysis was undertaken to determine the effect of Compound Ion TGF-β-induced CTGF and α-SMA (markers of fibrosis) on normal humandermal fibroblasts (NHDF).

Expression of the profibrotic (CTGF) and fibrotic markers (α-SMA) weredetermined by quantitative real-time PCR. As shown in Table 4, Compound1 inhibits by 99 and 85% the expression of mRNA of α-SMA and CTGF,respectively.

TABLE 4 Inhibition of α-SMA and CTGF mRNA expression in TGF-β inducedNHDF cells. α-SMA expression CTGF expression in NHDF cells in NHDF cells% of inhibition % of inhibition Compound Structure [mM] [mM] 1

99% [0.02] 85% [0.02]

Example 4 Antifibrotic Activity of Compound 1 in a Model of RenalFibrosis

Typical experimental models of kidney fibrosis in mice or rats includedb/db nephritic mice (models for diabetic nephropathy) and reflects thenephropathy observed in human. Evaluation of the effect of Compound 1 ondiabetic nephropathy was performed in a db/db mouse model. Briefly,total nephrectomy of the right kidney was performed on day 0 and db/dbmice (6-week old) were treated with vehicle or Compound 1 (10 and 50mg/kg, oral once a day) from day 1 and glomerular filtration rate (GFR)was measured on day 119 as a direct measure of kidney function. FIG. 1illustrates the reduction of GFR in db/db diabetic mouse compared toC57BL/6 mice (control mice), showing clearly the nephropathy associatedwith diabetes. Oral treatment with 10 and 50 mg/kg increases the GFRfunction of the kidney up to normal (C57BL/6) mouse, as shown in FIG. 1.This result clearly indicates that the treatment with Compound 1 reducesnephropathy and fibrosis of the kidney of the diabetic db/db mice.

All patents, patent applications, provisional applications, andpublications referred to or cited herein are incorporated by referencein their entirety, including all figures and tables, to the extent theyare not inconsistent with the explicit teachings of this specification.

It should be understood that the examples and embodiments describedherein are for illustrative purposes only and that various modificationsor changes in light thereof will be suggested to persons skilled in theart and are to be included within the spirit and purview of thisapplication.

1. A pharmaceutically acceptable salt of a compound represented by theformula:

wherein A is straight C₅ alkyl, straight C₆ alkyl, C₅ alkenyl, C₆alkenyl, C(O)—(CH₂)_(n)—CH₃ or CH(OH)—(CH₂)_(n)—CH₃ wherein n is 3 or 4;R₁ is H, For OH; R₂ is straight C₅ alkyl, straight C₆ alkyl, C₅ alkenyl,C₆ alkenyl, C(O)—(CH₂)_(n)—CH₃ or CH(OH)—(CH₂)_(n)—CH₃ wherein n is 3 or4; R₃ is H, F, OH or CH₂Ph; R₄ is H, F or OH; Q is 1) (CH₂)_(m)C(O)OHwherein m is 1 or 2, 2) CH(CH₃)C(O)OH, 3) C(CH₃)₂C(O)OH, 4)CH(F)—C(O)OH, 5) CF₂—C(O)OH, or 6) C(O)—C(O)OH.
 2. The compoundaccording to claim 1, wherein the pharmaceutically acceptable salt ofsaid compound is sodium, potassium, lithium, ammonium, calcium,magnesium, manganese, zinc, iron, or copper.
 3. The compound of claim 2,wherein the pharmaceutically acceptable salt of said compound is sodium.4. The compound according to claim 1 wherein said compound is one of thefollowing compounds:

or a pharmaceutically acceptable salt of said compound.
 5. A compoundthat is a free acid form or a pharmaceutically acceptable salt of one ofthe following compounds:


6. The compound of claim 5, which is a free acid form or apharmaceutically acceptable salt of Compound 1.